CLINICAL RESEARCH STUDIES

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1 CLINICAL RESEARCH STUDIES Family history of aortic disease predicts disease patterns and progression and is a significant influence on management strategies for patients and their relatives Chase R. Brown, BS, a Roy K. Greenberg, MD, a,b Shen Wong, MD, a Matthew Eagleton, MD, a Tara Mastracci, MD, a Adrian V. Hernandez, MD, PhD, c Christina M. Rigelsky, MS, CGC, d and Rocio Moran, MD, d Cleveland, Ohio Background: While a positive family history (FH) is a known risk factor for developing an aneurysm, its association with the extent of disease has not been established. We evaluated the influence of a FH of aortic disease with respect to the pattern and distribution of aortic aneurysms in a given patient. Methods and Results: From November 1999 to November 2011, 1263 patients were enrolled in physician-sponsored endovascular device trials to treat aortic aneurysms. Of the 555 patients who were alive and returning for follow-up, we obtained 426 (77%) family histories. Three-dimensional imaging studies were used to identify the presence of aneurysms; 36% (155/426) of patients had a FH of aortic aneurysms and 5% (21/155) had isolated intracranial aneurysms. A logistic regression model was used to compare aortic morphology between patients with a positive or negative FH for aneurysms. Patients with a positive FH of aortic aneurysms were younger at their initial aneurysm (63 vs 70 years; P <.0001), more frequently had proximal aortic involvement (root: odds ratio [OR], 5.4; P <.0001; ascending: OR, 2.9; P <.001; thoracic: OR, 2.2; P [.01) with over 50% of FH patients ultimately developing suprarenal aortic involvement (P [.0001) and had a greater incidence of bilateral iliac artery aneurysm (OR, 1.8; P [.03). Conclusions: FH is an important tool that provides insight into the expected behavior of the untreated aorta and has significant implications for the development of treatment strategies. These findings should be used to guide patient s management with regard to treatment, follow-up paradigms, genetic testing, and screening of other family members. (J Vasc Surg 2013;58: ) Aortic aneurysms and dissections claim 15,000-30,000 lives per year. 1 Despite the associated morbidity and mortality of the disease, the etiology and pathogenesis remains elusive to clinicians in most cases. Over the last several decades, the role of genetics in aortic aneurysms and dissections has been increasingly appreciated. 2-7 While the defined gene mutations that predispose to disease development are still being elucidated, a positive family history (FH) of aneurysmal disease can provide insight into which patients are at the greatest risk for a genetic etiology. 8,9 From the Department of Vascular Surgery, a Department of Thoracic and Cardiovascular Surgery, b Department of Qualitative Health Sciences, c and Genomic Medicine Institute, d Cleveland Clinic. Author conflict of interest: Dr Greenberg receives Intellectual Property Rights from Cook Medical. Reprint requests: Roy K. Greenberg, MD, Department of Vascular Surgery, Cleveland Clinic, 9500 Euclid Ave, Desk H-32, Cleveland, OH ( greenbr@ccf.org). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest /$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. Current knowledge dictates that between 15% and 30% of patients with an aortic aneurysm and/or dissection will have a positive FH Although the genetic mutations in such patients remain largely invisible, other factors, such as a younger age of disease onset and more aggressive aneurysm growth rate compared with patients without a FH of aortic disease have been noted. 11,14-16 Whether a positive FH can reveal additional information about patients aortic disease has not been rigorously studied. Based on clinical experience, it was hypothesized that patients with a positive FH have more extensive aortic aneurysms and a different pattern of disease than patients with no FH. To date no studies have attempted to analyze morphologic differences of aortic aneurysms based on a patient s FH. The objective of this study is to evaluate the influence of a FH of aortic disease to determine its impact on the pattern and extensiveness of aortic aneurysms in a given patient. METHODS Study patients. From November 1999 to November 2011, 1263 patients were enrolled in one of three physician-sponsored endovascular device trials (NIH no.: 573

2 574 Brown et al September 2013 Fig 1. Overall familial incidence of aneurysmal disease in probands with aortic aneurysms. ICA, Intracranial aneurysm. NCT , NCT , NCT ) intended to treat abdominal, thoracic, or thoracoabdominal aortic aneurysms. Within this cohort, 555 patients were alive and returning to the Cleveland Clinic for annual follow-up studies. Patients were interviewed to obtain a full FH analysis to determine the presence of family members with arterial aneurysms (aortic and/or intracranial). We completed a detailed FH on 426 (77%) patients, while 129 patients declined or were unable to provide information. Patients with a confirmed connective tissue disease were not included in this study. Study approval was granted by our institutional review board, and all patients enrolled signed an informed consent. Study design. Details for each patient regarding their type of aortic aneurysm, comorbidities, and outcomes were obtained from a prospectively collected database (Oracle Clinical). Patients were grouped based upon their FH of aneurysmal disease: (1) FH of aortic aneurysms, (2) FH of isolated intracranial aneurysms, and (3) no FH. Patients with a FH of aortic aneurysms were compared with the no FH group to determine differences in demographics, age at aneurysm presentation, number and location of aneurysmal segments, and frequency of previous aortic repairs. We then compared patients with a FH of isolated intracranial aneurysms to the no FH patients, in a similar fashion. Patients with a FH of aortic aneurysms were also stratified by the number of relatives in their FH with aortic disease (one family member vs two or more family members) and compared to determine if those with a greater number of relatives had more extensive aortic morphology. Additionally, these patients were grouped by their degree of relatedness to affected relatives (only first degree: parents, siblings, children; vs only second degree: aunts, uncles, grandparents) and similarly compared to determine differences. Ascertainment of FH. FHs were collected for each patient by in-person or phone interview. The FH data was ascertained by a clinical geneticist, genetic counselor, research nurse, or study investigator. To standardize the process, each research member who recorded FHs was trained by a clinical geneticist. A FH was constructed for each proband and data gathered on all first, second, and third-degree relatives. For each relative in the pedigree, the age/cause of death and past medical history specific to cardiovascular or aneurysm disease, connective tissue disorders, and other genetic abnormalities were

3 Volume 58, Number 3 Brown et al 575 Table I. Patient characteristics based on a FH of aortic aneurysms No. FH (n ¼ 250) a FH aortic aneurysm (n ¼ 155) a P value Age of aortic aneurysm presentation, years <.0001 b Age at first aortic repair, years <.0001 b Female 41 (16) 36 (23).09 Hypertension 212 (85) 135 (87).5 Coronary artery disease 79 (32) 56 (36).3 Hyperlipidemia 135 (54) 77 (50).4 Chronic renal failure 2 (1) 2 (1).6 Congestive heart failure 35 (14) 15 (12).3 Myocardial infarction 81 (32) 54 (34).7 CABG 60 (24) 31 (20).3 PTCA 34 (14) 27 (17).3 Peripheral vascular disease 23 (9) 14 (9).9 Deep vein thrombosis 18 (7) 12 (7).8 COPD 63 (25) 34 (22).5 Cerebral vascular accident 29 (12) 19 (12).8 Smoking Current 42 (17) 28 (18) Prior 170 (68) 102 (66) Never 20 (8) 20 (13) Unknown 18 (7) 5 (3).3 CABG, Coronary artery bypass graft; COPD, chronic obstructive pulmonary disease; FH, family history; PTCA, percutaneous transluminal angioplasty. a Continuous data are shown as mean 6 standard deviation and categoric data as number (%). b Statistically significant P value. recorded. If a relative was reported to have an aneurysm, additional information was asked of the patient to provide validity for the diagnosis (imaging studies, surgical reports, death certificates, or autopsy data). Excluding patients with cardiovascular disease, relatives reported deceased because of sudden death with an unknown etiology were considered to potentially have had an aneurysm. The interview process defined disease as the presence of aortic and/or intracranial aneurysms in any first, second, or third-degree relative. Family members that were reported deceased because of sudden death with unknown etiology were considered to potentially have had an aneurysm. Definition of aortic disease. A contrast-enhanced computed tomography scan 0 to 6 months prior to the endovascular repair was used to determine the extent and distribution of each patient s presenting aortic pathology. Standardized measurements were obtained for each aortic segment with three-dimensional imaging software and centerline of flow analysis (Tera Recon, Foster City, Calif). Aneurysmal segments were defined based on the following anatomic region and size thresholds: aortic root (>40 mm), ascending aorta (>40 mm), aortic arch (>40 mm), descending thoracic aorta (>40 mm), suprarenal aorta (>32 mm, defined by the diaphragm proximally), infrarenal aorta (>32 mm), right and left iliac arteries (>20 mm), right and left internal iliac arteries (>10 mm), and right and left femoral arteries (>15 mm). The patient s presenting aortic pathology was characterized based on previously reported guidelines and nomenclature. 17 The extensiveness of aneurysmal disease was defined as the number of aneurysmal segments present in each patient from imaging or areas of previous repair. Patient variables. Variables collected for each patient included age at presentation of first aneurysm, sex, presenting aortic pathology, location and number aneurysmal segments, number and proximity of family members with aneurysmal disease, details regarding pervious aortic repairs, hypertension, coronary artery disease, hyperlipidemia, congestive heart failure, chronic renal failure, myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, peripheral vascular disease, deep vein thrombosis, chronic obstructive pulmonary disease, cerebral vascular accident, and smoking history. Statistical analysis. Continuous variables, presented as mean 6 standard deviation, were compared using the Wilcoxon rank sum test and categorical variables, presented as percentages, were compared using the c 2 test. Univariate analyses were performed on patient characteristics and comorbidities between patients with and without a FH of aortic disease to determine statistically significant differences. Variables from the univariate analysis with a P #.20 were used in a logistic regression model to compare patients with and without a FH, and adjusted odds ratios (ORs) and P values were calculated. Significance was set for P #.05 and ORs presented at 95% confidence intervals (CIs). RESULTS Incidence for familial aneurysmal disease. The overall incidence of patients with a FH for any aneurysmal disease (aortic and/or intracranial) was 41% (176/426), with 36% (155/426) having a FH of aortic aneurysms and 5% (21/426) having a FH of isolated intracranial aneurysms (Fig 1). The prevalence of dissection-related aneurysms was 5.4% (23/42), with 16 having a FH and

4 576 Brown et al September 2013 Fig 2. Incidence of patients with aneurysmal segments in the aorta based on family history (FH) of aortic disease. The asterisk represents statistically significant differences based on adjusted P values. seven no FH; 2.5% (11/426) of all patients had both aortic and intracranial aneurysm and were considered part of the FH of aortic aneurysm group. Impact of FH of aortic disease on patient demographics. Patients with a FH of aortic aneurysms were younger at the initial presentation of their aortic disease and at their first aortic repair as compared with those with no FH (P <.001) (Table I). While a higher percentage of females was present in the patients with a FH of aortic disease compared with the no FH group, this did not reach statistical significance (FH, 23%; no FH, 16%; P ¼.09). Additionally, there were no statistically significant differences in the rate of smoking, hypertension, hyperlipidemia, coronary artery disease, and chronic obstructive pulmonary disease. Patient demographics are presented in Table I. Impact of a FH of aortic disease on proband. A logistic regression model was used to determine the association between a FH and the distribution and extensiveness of the proband s aneurysmal disease. Based on the univariate analysis, age at aneurysm presentation and sex were added to the model to control for confounding variables. Our data indicates that the presence of a positive FH of aortic aneurysms influences the pattern and anatomic distribution of aneurysms in the proband s aorta and iliofemoral arteries. While both the FH of aortic aneurysm and no FH groups had a similar incidence of infrarenal aneurysms (FH, 87% vs no FH, 88%; P ¼.8), the presence of a positive FH significantly increased the likelihood of developing aneurysmal disease in the aortic root (P <.0001), ascending aorta (P <.0001), descending thoracic aorta (P ¼.01), and suprarenal aorta (P ¼.0001) (Fig 2). Such patients also had a significantly greater incidence of aneurysms in bilateral iliac arteries (P ¼.03) and in a unilateral internal iliac artery (P ¼.02) (Fig 3). Adjusted ORs for developing disease in the aorta and iliofemoral arteries based on FH are shown in Table II. Additionally, patients with a FH of aortic disease had more extensive aneurysms than with no FH, as determined by the number of aneurysmal segments present in aorta and Fig 3. Incidence of patients with aneurysmal segments in the iliofemoral arteries based on family history (FH) of aortic aneurysms. The asterisk represents statistically significant differences based on adjusted P values. iliofemoral arteries. Fig 4 illustrates that patients with a FH of aortic aneurysms had a greater number of aneurysmal segments (median, 3; interquartile range [IQR], 2-5) compared with those with no FH (median, 2; IQR, 1-3; P <.001). Furthermore, the frequency of previous aortic repairs was greater in patients with a FH (41%) compared those with no FH (24%; P ¼.003). Impact of a FH of intracranial aneurysms on proband. Similar to the FH of aortic aneurysm group, patients with a FH of isolated intracranial aneurysms (n ¼ 21) presented with an aortic aneurysm at a younger age (P ¼.03) (Table III). Additionally, these patients more often had proximal distribution of disease in the aortic root (P ¼.001), ascending aorta (P ¼.01), and descending thoracic aorta (P ¼.001), compared with patients with no FH (Table III). Patients with a FH of intracranial aneurysms also had more extensive aneurysmal disease. As presented in Fig 4, these patients had a greater number of aneurysmal segments (median, 4; IQR, 1-6) that were present throughout the aorta and iliofemoral arteries as compared to the no FH group (median, 2; IQR, 1-3; P ¼.002). Impact of the number of relatives with aortic disease on the proband. Patients with a FH of aortic disease were dichotomized into patients with only one affected family member (n ¼ 61) and those with two or more affected family members (n ¼ 94) with aortic disease. Both groups had a greater frequency of aneurysms in the aortic root, ascending aorta, descending thoracic aorta, suprarenal aorta, bilateral iliac arteries, and a unilateral internal iliac artery. However, compared with patients with only one family member with aortic disease, patients with two or more family members had a greater likelihood of developing disease in the aortic root (OR, 2.54; 95% CI, ), suprarenal aorta (OR, 2.2; 95% CI, ), and bilateral iliac arteries (OR, 2.4; 95% CI, ) (Figs 5 and 6) when compared with patients with only one relative with a positive FH.

5 Volume 58, Number 3 Brown et al 577 Table II. Impact of FH of aortic disease on the distribution of aneurysms in the proband No FH (n ¼ 250), No. % FH aortic aneurysm (n ¼ 155), No. % Adjusted P value Adjusted ORs (95% CI) Aortic segments Root 22 (9) 55 (35) <.0001 a 5.4 ( ) Ascending 35 (14) 57 (37) <.0001 a 2.9 ( ) Arch 16 (6) 25 (16) ( ) Thoracic 50 (20) 57 (37).01 a 2.2 ( ) Suprarenal 83 (33) 87 (56).0001 a 2.3 ( ) Infrarenal 221 (88) 135 (87) ( ) Iliofemoral segments Iliac artery Unilateral 50 (20) 25 (16) ( ) Bilateral 41 (16) 41 (26).03 a 1.8 ( ) Internal iliac artery Unilateral 1 (4) 18 (12).02 a 2.8 ( ) Bilateral 18 (7) 14 (9) ( ) Femoral artery Unilateral 6 (2) 7 (5) ( ) Bilateral 4 (2) 3 (2) ( ) CI, Confidence interval; FH, family history; OR, odds ratio. a Statistically significant P value. Correspondingly, patients with two or more family members with disease had even more extensive aneurysmal disease. The median number of aneurysmal segments was 4 (IQR, 3-6) for patients with two or more family members and was three (IQR, 2-5) for those with only one family member (P <.008). No difference was found between groups in the age at presentation of aortic aneurysm (two or more family members, vs one family member, ; P ¼.5). Impact of proximity of relative (degree of relatedness) on the proband. Patients with a FH of aortic disease were dichotomized into patients with only a first-degree relative (n ¼ 106) and those with only a second-degree relative (n ¼ 19). These groups were then compared to determine differences in the distribution and extensiveness of a proband s aneurysmal disease. Regardless of the proximity of the relative to the proband, both groups had a similar incidence of disease in all aortic or iliofemoral segments. Fig 7 presents the distribution of aneurysmal disease for patients with only a first-degree relative compared with those with only a second-degree relative, and no identifiable differences were noted. Furthermore, the proximity of the relative to the proband does not influence the extensiveness of disease. Regardless if the patient had only a first or second-degree relative, the median number of aneurysmal segments was three (IQR, 2-5; P ¼.7). DISCUSSION Although a FH of aneurysmal disease is an established risk factor in the development of aortic aneurysmal disease, 8,18 little has been reported on the association between FH and the anatomic distribution and extensiveness of aneurysmal disease. In our investigation, precise anatomic data of the entire aorta and the iliofemoral Fig 4. Box plot demonstrating the number of aneurysmal segments present in the aorta and/or iliofemoral arteries based on family history (FH) of aneurysmal disease. ICA, Intracranial aneurysm. arteries were obtained and compared based on the presence or absence of a FH for aortic aneurysms. Our findings suggest that patients with a FH have (1) a younger presentation of aortic disease, (2) increased number of aneurysmal segments, (3) greater likelihood of developing aneurysmal disease proximal to the infrarenal aorta, (4) increased occurrence of bilateral common iliac and unilateral internal iliac artery aneurysms, and (5) higher frequency of previous aortic repairs. Interestingly, these trends were magnified as the number of affected family members increased and were detected in FH patients irrespective of whether a first or second-degree relative was present.

6 578 Brown et al September 2013 Table III. Impact of FH of intracranial aneurysms on the distribution of aneurysms in the proband No. FH FH isolated intracranial (n ¼ 250) a aneurysm (n ¼ 21) a Adjusted P value Adjusted ORs (95% CI) Age of aneurysm presentation b NA Aortic segments Root 22 (9) 8 (38).001 b 6.8 ( ) Ascending 35 (14) 8 (38).01 b 3.9 ( ) Arch 16 (6) 3 (14) ( ) Thoracic 50 (20) 12 (57).001 b 4.8 ( ) Suprarenal 83 (33) 11 (52) ( ) Infrarenal 221 (88) 17 (81) ( ) Iliofemoral segments Iliac artery Unilateral 50 (20) 2 (10) ( ) Bilateral 41 (16) 6 (29) (0.7-54) Internal iliac artery Unilateral 11 (4) 1 (5) ( ) Bilateral 18 (7) 3 (14) ( ) Femoral artery Unilateral 6 (2) 0 (0).9 0 ( ) Bilateral 4 (2) 0 (0).7 0 ( ) CI, Confidence interval; FH, family history; OR, odds ratio. a Continuous data are shown as mean 6 standard deviation and categoric data as number (%). b Statistically significant P value. In 1989, Darling et al investigated the association of aortic aneurysm morphology (aortic vs aortoiliac involvement) between patients with and without a FH of disease. 14 Unsurprisingly, no difference was found, as they used type of repair as their anatomic surrogate rather than precise anatomic measurements for their analysis and provided no information above the infrarenal segment. However, similar to our findings, they did determine that the FH group had a younger onset of aortic disease. More recently, Albornoz et al demonstrated that patients with thoracic aneurysms and a positive FH have a more aggressive growth rate of their aneurysm than in patients with sporadic disease. 11 Such findings, in addition to our own, suggest that in patients with a positive FH, genetic factors may prominently contribute to the degenerative and environmental processes involved in aneurysmal pathogenesis than previously recognized. The association between genetics and distribution of aneurysmal disease is most clearly observed in syndromic connective tissue diseases (CTDs) such as Marfans, TGFBR1/2 mutations (eg, Loeys-Dietz), and type IV Ehlers-Danlos syndromes. In these diseases, specifically defined genetic mutations lead to aortic pathology at a relatively young age (<40 years). 19 In addition, there has been growing appreciation for another group of CTDs affecting the proximal and thoracic aorta in whom genetic mechanisms are less clearly defined, termed familial thoracic aortic aneurysm and dissection. 2,4,6,7,20 In these patients, aortic aneurysms occur at a later age than the syndromic CTDs, albeit younger than in sporadic cases. Furthermore, there appears to be a group of patients with abdominal aortic aneurysms and a strong FH but have an even more poorly defined genetic mechanism. 5,21,22 These observations provide support for the concept that there is a spectrum of CTD, with the genetically defined syndromic diseases at one end and those with an undiagnosed genetic defect but an extensive FH at the other. Within this spectrum, the presence of a positive FH may provide the evidence for a genetic causation, except in cases of spontaneous mutations. Such phenotypic variations in aortic morphology among patients are likely due to different gene mutations, decreased penetrance, and variable expression, 3,23,24 which ultimately has implications on the potential benefits of molecular testing of family members as well as the overall management strategy for the patient. Abnormalities in connective tissues likely affect the entire aortic tree, rendering it more vulnerable to accumulated environmental and degenerative factors with increasing age. Our data illustrate that patients with a FH of aortic and/or intracranial aneurysms assists in identifying patients that are at greater risk for proximal disease progression. Additionally, we noted that patients with a FH of aortic disease have a greater occurrence of bilateral iliac artery and unilateral internal iliac artery aneurysms. The bilateral distribution is consistent with the idea of global arterial susceptibility conferred by connective tissue abnormality rather than sporadic disease secondary to a predominantly degenerative causation. Recent investigations into multiple familial thoracic aortic aneurysm and dissection family members demonstrated a significant proportion of individuals suffering from bilateral iliac aneurysms. 4,20 This further strengthens the concept that connective tissue abnormalities from genetic mutations and positive FH are interrelated. Although Larsson et al suggested that having more than one diseased relative increases the risk of developing an aneurysm, 12 no previous studies have investigated the association between the number of affected family members and the pattern and extent of a patient s aneurysmal disease. Our analysis illustrates that patients with

7 Volume 58, Number 3 Brown et al 579 Fig 5. Incidence of aneurysmal segments in the aorta for patients with two family members compared with patients with only one family member with aortic disease. The asterisk represents statistically significant differences based on adjusted P values. two or more relatives had a greater likelihood of developing an increased number of aneurysmal segments in the aortic root, suprarenal aorta, and bilateral iliac arteries than in patients with only one diseased relative (Figs 5 and 6). Thus, when obtaining a patient s FH, a suspicion for more extensive disease should be greater when a patient has multiple affected family members. The majority of studies to date investigating patients with a FH of aortic disease have limited the focus to firstdegree relatives. 11,12,14,25 This may relate to a paradigm of thinking adapted from observed autosomal dominant inheritance patterns in syndromic connective tissue disease. In speculating that the inheritance patterns may be complex with decreased penetrance, our FH analysis also included second- and third-degree relatives. We detected no demonstrable difference in the extensiveness or distribution of aneurysmal disease between patients with only an affected second-degree relative compared with only a first-degree relative. While the power of this analysis was limited by the small number of patients with only an affected seconddegree relative (n ¼ 19), we believe there remains clinical utility in obtaining family histories beyond the first degree to adjust follow-up and treatment paradigms accordingly. Patients with a positive FH are generally younger and have a greater proclivity to develop disease proximal to the infrarenal aorta. Logically, any repair strategy must account for these occurrences in such patients. Traditionally, open repair has been the treatment of choice in young patients with connective tissue disease related pathology. 19 However, late failure in open surgical repairs of infrarenal aortic aneurysms has been significantly associated with a positive FH of aneurysmal disease and more extensive disease present at the time of the initial infrarenal repair. 13 Additionally, our results indicate that patients with a FH had a greater frequency of previous aortic repairs compared with the no FH group, suggesting that a definitive plan for future reinterventions must be considered during the initial repair. Given that a FH has been shown to be a risk factor Fig 6. Incidence of aneurysmal segments in the iliofemoral arteries for patients with two family members compared with patients with only one family member with aortic disease. The asterisk represents statistically significant differences based on adjusted P values. Fig 7. Incidence of aneurysmal segments for patients with only a first-degree relative compared with patients with only a seconddegree relative with aortic disease. No significant differences were identified. for late failures in open repair, with the proximal anastomosis being the most common site of failure, data suggests that the aneurysmal neck in such patients is the area of highest vulnerability. 13,26 This effect may be amplified by landing a stent graft, or sewing an anastomosis into the aorta, which is not frankly aneurysmal but ectatic or has irregular signs of impending dilation. In addition to other considerations in FH patients, landing zone selection is of paramount importance for the durability of repair. What options will the surgeon have for repair as the initial proximal landing zone fails? The best answer is likely avoidance of the problemdtry to treat above the disease to a level that if further failure occurs, it is simple to carry out more proximal treatment. This would require one to treat the entire visceral segment, rather landing somewhere in the midst of the renal and visceral vesselsdwhether accomplished with an endovascular or open surgical approach. This would involve the use of fenestrations and

8 580 Brown et al September 2013 branched devices to reach the more resilient aorta, by allowing extension through the visceral segment, or open surgery whereby each visceral and renal are implanted separately into a side-arm graft. Nonetheless, progression of disease may still lead to late failure at the proximal seal zone, and these patients must be closely followed. There are several limitations in this study. In our cohort, 36% of patients had a positive FH of aortic disease, which may reflect this specific referral patient population. Since we did not have a means of confirming a family member s aneurysmal disease, some of the historical data may be inaccurate. Nonetheless, it seems more likely that data would be skewed against a positive FH, given the number of relatives who died of a heart attack and the lack of imaging in all relatives. Thus, some relatives likely had an aneurysm that was never identified. However, the opposite was true for family members with sudden death, where it was assumed that they did have an aortic aneurysm. Of 176 patients that claimed to have a positive FH, only 16 (9%) were due to sudden death. Although such inclusion may be criticized in that the death may be from other causes, particularly cardiovascular, these patients were included in the FH group due to the high suspicion of aneurysms in these relatives. Reassuringly, statistical analysis of our results with and without patients with a FH of sudden death was equivalent. CONCLUSIONS Traditionally, obtaining a detailed FH for patients with an aortic aneurysm has provided two main functions: (1) provides evidence for a potential genetic etiology of disease; and (2) indicates the need for screening other family members. However, this study suggests that obtaining an accurate FH for patients with aortic disease is a much more powerful tool than simple screening. FH can assist in predicting the potential pattern and extensiveness of the aneurysm for a given patient. The information may alter management strategies ensuring that clinicians aggressively search for healthy aorta, given the greater potential for proximal degeneration. Finally, FH patients provide an enticing study group for further investigation regarding the molecular mechanisms of their disease. Ultimately, this simple tool (FH) will assist in the evaluation, treatment, and subsequent follow-up of all patients with aneurysmal disease. AUTHOR CONTRIBUTIONS Conception and design: CB, RG, ME, TM Analysis and interpretation: CB, RG, SW, ME, TM, CR, RM Data collection: CB, SW, CR, RM Writing the article: CB, RG Critical revision of the article: RG, ME, TM, CR, RM Final approval of the article: CB, RG, SW, ME, TM, AH, CR, RM Statistical analysis: CB, AH Obtained funding: RG Overall responsibility: RK REFERENCES 1. National Vital Statistics Reports. 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